Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors

ABSTRACT

The present invention provides a compound of formula I; 
                         
or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , A 1 , X, X 1 , s and n are defined herein. The invention also relates to a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides pharmaceutical composition of the compounds of the invention and a combination of pharmacologically active agents and a compound of the invention.

This application claims benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/414,163, filed Nov. 16, 2010, the contentof which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Endogenous atrial natriuretic peptides (ANP), also called atrialnatriuretic factors (ANF) have diuretic, natriuretic and vasorelaxantfunctions in mammals. The natural ANF peptides are metabolicallyinactivated, in particular by a degrading enzyme which has beenrecognized to correspond to the enzyme neutral endopeptidase (NEP) EC3.4.24.11, also responsible for e.g. the metabolic inactivation ofenkephalins.

Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP)is a zinc-containing metalloprotease that cleaves a variety of peptidesubstrates on the amino side of hydrophobic residues [see Pharmacol Rev,Vol. 45, p. 87 (1993)]. Substrates for this enzyme include, but are notlimited to, atrial natriuretic peptide (ANP, also known as ANF), brainnatriuretic peptide (BNP), met- and leu-enkephalin, bradykinin,neurokinin A, endothelin-1 and substance P. ANP is a potent vasorelaxantand natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001)].Infusion of ANP in normal subjects resulted in a reproducible, markedenhancement of natriuresis and diuresis, including increases infractional excretion of sodium, urinary flow rate and glomerularfiltration rate [see J Clin Pharmacol, Vol. 27, p. 927 (1987)]. However,ANP has a short half-life in circulation, and NEP in kidney cortexmembranes has been shown to be the major enzyme responsible fordegrading this peptide [see Peptides, Vol. 9, p. 173 (1988)]. Thus,inhibitors of NEP (neutral endopeptidase inhibitors, NEPi) shouldincrease plasma levels of ANP and, hence, are expected to inducenatriuretic and diuretic effects.

This enzyme is involved in the breakdown of several bioactiveoligopeptides, cleaving peptide bonds on the amino side of hydrophobicamino acid residues. The peptides metabolised include atrial natriureticpeptides (ANP), bombesin, bradykinin, calcitonin gene-related peptide,endothelins, enkephalins, neurotensin, substance P and vasoactiveintestinal peptide. Some of these peptides have potent vasodilatory andneurohormone functions, diuretic and natriuretic activity or mediatebehaviour effects.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide novel compounds which areuseful as neutral endopeptidase inhibitors, e.g. as inhibitors of theANF-degrading enzyme in mammals, so as to prolong and potentiate thediuretic, natriuretic and vasodilator properties of ANF in mammals, byinhibiting the degradation thereof to less active metabolites. Thecompounds of this invention are thus particularly useful for thetreatment of conditions and disorders responsive to the inhibition ofneutral endopeptidase (NEP) EC 3.4.24.11.

The compounds of the invention have increased neutral endopeptidaseinhibitory activity compared to the compounds of the U.S. Pat. No.5,217,996.

The invention pertains to the compounds, pharmaceutical compositions andmethods of use thereof as described herein. Examples of compounds of theinvention include the compounds according to anyone of Formulae I to V,or a pharmaceutically acceptable salt thereof and the compounds of theexamples.

The invention therefore provides a compound of the formula (I):

wherein:X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl;R¹ is H or C₁₋₆ alkyl;R² for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl;A¹ is a linear C₁₋₄ alkylene;R³ for each occurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo,C₁₋₇alkyl or halo-C₁₋₇alkyl; orn is an integer from 1 to 5;s is 0 or an integer from 1 to 4; ora pharmaceutically acceptable salt thereof.

The compounds of the invention, by inhibiting the neutral endopeptidaseEC.3.4.24.11, can potentiate the biological effects of bioactivepeptides. Thus, in particular the compounds have utility in thetreatment of a number of disorders, including hypertension, pulmonaryhypertension, pulmonary arterial hypertension, isolated systolichypertension, resistant hypertension, peripheral vascular disease, heartfailure, congestive heart failure, left ventricular hypertrophy, angina,renal insufficiency (diabetic or non-diabetic), renal failure (includingedema and salt retension), diabetic nephropathy, non-diabeticnephropathy, constrast induced nephropathy, nephroic syndrome,glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea ofprimary renal disease, renal vascular hypertention, diabetic retinopathyand end-stage renal disease (ESRD), endothelial dysfunction, diastolicdysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy,supraventricular and ventricular arrhythmias, atrial fibrillation (AF),cardiac fibrosis, atrial flutter, detrimental vascular remodeling,plaque stabilization, myocardial infarction (MI), renal fibrosis,polycystic kidney disease (PKD), renal failure (including edema and saltretension), cyclical oedema, Meniéres disease, hyperaldosteroneism(primary and secondary) and hypercalciuria, ascites. In addition,because of their ability to potentiate the effects of ANF the compoundshave utility in the treatment of glaucoma. As a further result of theirability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compoundsof the invention may have activity in other therapeutic areas includingfor example the treatment of menstrual disorders, preterm labour,pre-eclampsia, endometriosis, and reproductive disorders (especiallymale and female infertility, polycystic ovarian syndrome, implantationfailure). Also the compounds of the invention should treat asthma,obstructive sleep apnea, inflammation, leukemia, pain, epilepsy,affective disorders such as depression and psychotic condition such asdementia and geriatric confusion, obesity and gastrointestinal disorders(especially diarrhea and irritable bowel syndrome), wound healing(especially diabetic and venous ulcers and pressure sores), septicshock, gastric acid secretion dysfunction, hyperreninaemia, cysticfibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabeticcomplications and athereosclerosis, male and female sexual dysfunction.

In a preferred embodiment the compounds of the invention are useful inthe treatment of cardiovascular disorders.

In another embodiment, the invention pertains to a method for treating adisorders or diseases responsive to the inhibition of neutralendopeptidase EC 3.4. 24.11 (NEP), in a subject in need of suchtreatment, comprising: administering to the subject an effective amountof a compound according to anyone of Formulae I-V, or a pharmaceuticallyacceptable salt thereof, such that the disorder or disease responsive tothe inhibition of neutral endopeptidase EC 3.4. 24.11 (NEP) in thesubject is treated.

In yet another embodiment, the invention pertains to pharmaceuticalcompositions, comprising a compound according to anyone of Formulae I-V,or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.

In still another embodiment, the invention pertains to combinationsincluding, a compound according to anyone of Formulae I-V, or apharmaceutically acceptable salt thereof, and pharmaceuticalcombinations of one or more therapeutically active agents.

In another embodiment, the invention pertains to a method for inhibitingneutral endopeptidase EC 3.4. 24.11 in a subject in need thereof,comprising: administering to the subject a therapeutically effectiveamount of a compound according to anyone of Formulae I-V, or apharmaceutically acceptable salt thereof, such that neutralendopeptidase EC 3.4. 24.11 is inhibited.

DETAILED DESCRIPTION OF THE INVENTION Definition

For purposes of interpreting this specification, the followingdefinitions will apply unless specified otherwise and wheneverappropriate, terms used in the singular will also include the plural andvice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched (or straight chain or linear) hydrocarbon moiety, comprising1 to 20 carbon atoms. Preferably the alkyl comprises 1 to 6 carbonatoms, and more preferably 1 to 4 carbon atoms. Representative examplesof alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,n-heptyl. The term “C₁₋₆alkyl” refers to a hydrocarbon having from oneto six carbon atoms. The term “C₁₋₇alkyl” refers to a hydrocarbon havingfrom one to seven carbon atoms. The term “alkylene” refers to a divalentalkyl radical, wherein alkyl is as previously defined.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalky andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Preferably, thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Representative examples of haloalkyl are fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms. The term“halo-C₁₋₆alkyl” refers to a hydrocarbon having one to six carbon atomsand being substituted by one or more halo groups. The term“halo-C₁₋₇alkyl” refers to a hydrocarbon having one to seven carbonatoms and being substituted by one or more halo groups.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-6, more preferablyabout 1-4 carbons. The term “C₁₋₇alkoxy” refers to an alkoxy grouphaving from one to seven carbon atoms. Similarly, the term “C₁₋₆alkyl”refers to a hydrocarbon having from one to six carbon atoms.

The term “halogen” or “halo” includes fluoro, bromo, chloro and iodo.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

Compound of the Invention:

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

Certain compounds of Formula I have the specific stereochemistry ofFormula II:

wherein:X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl;R¹ is H or C₁₋₆ alkyl;R² for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl;A¹ is a linear C₁₋₄ alkylene;R³ for each occurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo,C₁₋₇alkyl or halo-C₁₋₇alkyl; orn is an integer from 1 to 5;s is 0 or an integer from 1 to 4; ora pharmaceutically acceptable salt thereof.

Certain compounds of Formulae I wherein R² is halo and is attached tothe meta position and the other optional R² groups are independentlyC₁₋₆-alkoxy, hydroxy, halo, C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl. Thisembodiment is illustrated by compounds of Formulae III:

a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, X, X¹,A¹ and s have the definition of Formula I, supra and p is 0, 1, 2, 3 or4 and R^(2a) is halo.

In one aspect of this embodiment, the invention pertains to compound ofFormula III having the stereochemistry of Formula IV:

a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, X, X¹,A¹ and s have the definition of Formula I, supra and p is 0, 1, 2, 3 or4 and R^(2a) is halo.

In one embodiment, the invention pertains to compounds of Formula III orIV wherein R^(2a) is chloro. In a further aspect of this embodiment, theinvention pertains to compounds of Formula III or IV wherein R^(2a) ischloro and p is 0.

Certain compounds of Formula I wherein R² is C₁₋₅-alkoxy and is attachedto the ortho position and the other optional R² groups are independentlyC₁₋₆-alkoxy, hydroxy, halo, cyano or halo-C₁₋₆-alkyl. This embodiment isillustrated by compounds of Formulae V:

a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, X, X¹,A¹ and s have the definition of Formula I, supra and p is 0, 1, 2, 3 or4 and R^(2b) is C₁₋₆-alkoxy.

In one embodiment, the invention pertains to compounds of Formula Vwherein R^(2b) is methoxy. In a further embodiment, the inventionpertains to compounds of Formula V wherein R^(2b) is methoxy and p is 0.

The following embodiments can be used independently, collectively or inany combination or sub-combination:

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone of the classes orsubclasses described supra, wherein X and X¹ are independently OH orO—C₁₋₆-alkyl, or a pharmaceutically acceptable salt thereof. In oneaspect of this embodiment, the invention pertains to compound accordingto anyone of Formulae I to V, wherein X and X¹ are OH, or apharmaceutically acceptable salt thereof.

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone of the classes orsubclasses described supra, wherein R¹ is C₁₋₆-alkyl, or apharmaceutically acceptable salt thereof.

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone of the classes orsubclasses described supra, wherein A¹ is CH₂—CH₂, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone of the classes orsubclasses described supra, wherein s is 0, or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone of the classes orsubclasses described supra, wherein:

X and X¹ represent independently OH or O—C₁₋₆-alkyl;

R¹ is H or C₁₋₆-alkyl;

A¹ is CH₂—CH₂;

s is 0;

a pharmaceutically acceptable salt thereof.

In one embodiment, the invention pertains to compound according toanyone of Formulae I to V, or according to anyone classes or subclassesdescribed supra, wherein:

X and X¹ represent independently OH or O—C₁₋₆-alkyl;

R¹ is C₁₋₆-alkyl;

A¹ is CH₂—CH₂;

s is 0;

a pharmaceutically acceptable salt thereof.

In another embodiment R¹, R², R³, A¹, X, X¹, s and n groups are thosedefined by the R¹, R², R³, A¹, X, X¹, s and n groups in the Examplessection below.

In another embodiment individual compounds according to the inventionare those listed in the Examples section below or a pharmaceuticallyacceptable salt thereof.

It will be noted that the structure of some of the compounds of thisinvention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R, S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable. In many cases, the compounds of the presentinvention are capable of forming acid and/or base salts by virtue of thepresence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,sulfosalicylic acid, and the like. Pharmaceutically acceptable baseaddition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. For example, anyhydrogen represented by “H” in any of the formulae herein is intended torepresent all isotopic forms of hydrogen (e.g. ¹H, ²H or D, ³H); anycarbon represented by “C” in any of the formulae herein is intended torepresent all isotopic forms of carbon (e.g. ¹¹C, ¹³C_(;) ¹⁴C); anynitrogen represented by “N” is intended to represent all isotopic formsof nitrogen (e.g. ¹⁴N; ¹⁵N). N) Other examples of isotopes that areincluded in the invention include isotopes of oxygen, sulfur,phosphorous, fluorine, iodine and chlorine, such as ¹⁸F ³¹P, ³²P, ³⁵S,³⁶Cl, ¹²⁵I. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C are present. In one embodiment, theatoms in the formulae herein occur in their natural abundance. Inanother embodiment, one or more hydrogen atom may be enriched in ²H;or/and one or more carbon atom may be enriched in ¹¹C, ¹³C or ¹⁴C;or/and one or more nitrogen may be enriched in ¹⁴N. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, enrichment with heavier isotopes, particularly deuterium (i.e.,²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formulae I to V. The concentration ofsuch a heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-enriched compounds of formulae I to V can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-enriched reagent inplace of the non-enriched reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds according to anyone offormulae I to V that contain groups capable of acting as donors and/oracceptors for hydrogen bonds may be capable of forming co-crystals withsuitable co-crystal formers. These co-crystals may be prepared fromcompounds according to anyone of formulae I to V by known co-crystalforming procedures. Such procedures include grinding, heating,co-subliming, co-melting, or contacting in solution compounds accordingto anyone of formulae I to V with the co-crystal former undercrystallization conditions and isolating co-crystals thereby formed.Suitable co-crystal formers include those described in WO 2004/078163.Hence the invention further provides co-crystals comprising a compoundaccording to anyone of formulae I to V or a pharmaceutically acceptablesalt thereof.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or amelioration of a symptom, alleviation of a condition, slowor delay disease progression, or prevention of a disease, etc. In onenon-limiting embodiment, the term “a therapeutically effective amount”refers to the amount of the compound of the present invention that, whenadministered to a subject, is effective to (1) at least partiallyalleviate, inhibit, prevent and/or ameliorate a condition, a disorder ora disease or a symptom thereof (i) ameliorated by the inhibition ofneutral endopeptidase EC 3.4. 24.11 or (ii) associated with neutralendopeptidase EC 3.4. 24.11 activity, or (iii) characterized by abnormalactivity of neutral endopeptidase EC 3.4. 24.11; or (2) reduce orinhibit the activity of neutral endopeptidase EC 3.4. 24.11; or (3)reduce or inhibit the expression of neutral endopeptidase EC 3.4. 24.11.In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reduce or inhibit the activity of neutral endopeptidase EC3.4. 24.11; or at least partially reduce or inhibit the expression ofneutral endopeptidase EC 3.4. 24.11

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity. Carrier prodrugs are drugcompounds that contain a transport moiety, e.g., that improve uptakeand/or localized delivery to a site(s) of action. Desirably for such acarrier prodrug, the linkage between the drug moiety and the transportmoiety is a covalent bond, the prodrug is inactive or less active thanthe drug compound, and any released transport moiety is acceptablynon-toxic. For prodrugs where the transport moiety is intended toenhance uptake, typically the release of the transport moiety should berapid. In other cases, it is desirable to utilize a moiety that providesslow release, e.g., certain polymers or other moieties, such ascyclodextrins. Carrier prodrugs can, for example, be used to improve oneor more of the following properties: increased lipophilicity, increasedduration of pharmacological effects, increased site-specificity,decreased toxicity and adverse reactions, and/or improvement in drugformulation (e.g., stability, water solubility, suppression of anundesirable organoleptic or physiochemical property). For example,lipophilicity can be increased by esterification of (a) hydroxyl groupswith lipophilic carboxylic acids (e.g., a carboxylic acid having atleast one lipophilic moiety), or (b) carboxylic acid groups withlipophilic alcohols (e.g., an alcohol having at least one lipophilicmoiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as theω-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

General Synthetic Scheme:

The compounds of the invention can be synthesized using the methodsdescribed in the following schemes, examples, and by using artrecognized techniques. All compounds described herein are included inthe invention as compounds. Compounds of the invention may besynthesized according to at least one of the methods described inschemes 1-3.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999.

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkalimetal or alkaline earth metal compounds, such as the correspondinghydroxides, carbonates or hydrogen carbonates, such as sodium orpotassium hydroxide, carbonate or hydrogen carbonate, with correspondingcalcium compounds or with ammonia or a suitable organic amine,stoichiometric amounts or only a small excess of the salt-forming agentpreferably being used. Acid addition salts of compounds of the presentinvention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by e.g. medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, including those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, including, for example, solvents or diluents thatare inert towards the reagents used and dissolve them, in the absence orpresence of catalysts, condensation or neutralizing agents, for exampleion exchangers, such as cation exchangers, e.g. in the H+ form,depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

Typically, the compounds according to of formulae I to V can be preparedaccording to the Scheme provided infra.

The compounds of the invention of formula II can be prepared byhydrolysis of intermediates A to C wherein X, X¹, A¹, R¹, R², R³, s andn have the definition of Formula I, supra; and P¹ and P² are appropriateprotecting groups selected from, but not limited to, methyl, ethyl,isopropyl, tert-butyl, methoxybenzyl or benzyl.

Standard methods can be applied for the hydrolysis of Intermediates A toC using a base selected from, but not limited to, NaOH, KOH or LiOH, oran acid selected from, but not limited to, TFA or HCl. When P¹ or P² isbenzyl or methoxybenzyl, preferable method of deprotection ishydrogenation in the presence of a catalyst such as, but not limited to,palladium-on-carbon under hydrogen.

The intermediate A, B or C can be prepared using the following processcomprising: condensing an intermediate D or E wherein X, P¹, R¹, R² andn are as previously described:

with an intermediate F, G or H wherein X¹, A¹ and P² are previouslydescribed.

Known condensation methods may be applied including, but not limited to,conversion of the intermediate F or G to their corresponding acidhalide, using reagents such as thionyl chloride or oxalyl chloride, orconversion of intermediate F or G to mixed anhydride using reagents suchas CIC(O)O-isobutyl or 2,4,6-trichlorobenzoyl chloride followed byreaction of the acid halide or mixed anhydride with the intermediate Dor E in a presence or absence of a base such as tertiary amine (e.g.triethylamine, DIPEA, or N-methylmorpholine) or pyridine derivative(e.g. pyridine, 4-(dimethylamino)pyridine, or 4-pyrrolidinopyridine).Alternatively, the intermediate D or E can be coupled with F or G usingcoupling reagents such as DCC, EDCI, PyBOP or BOP in presence or absenceof a reagent such as 1-hydroxybenazotriazole,1-hydroxy-7-azabenzotriazole or pentafluorophenol. Alternatively,Intermediate D or E can be reacted with intermediate H in the presenceof a base such as, but not limited to, pyridine, triethylamine anddiisopropylethylamine.

Scheme 1 illustrates the synthesis of intermediate D or E which isuseful for the preparation of compounds of Formula I.

Aldehyde I is prepared by reduction of a protected amino acid ester witha reducing agent such as, but not limited to, diisobutyl aluminumhydride. The protecting group P₃ can be chosen from, but not limited to,Boc or Cbz and group Y can be chosen from, but not limited to, halogenor triflate. Intermediate J is prepared from intermediate I bymethodology such as, but not limited to, a Wittig reaction employing anappropriate phosphorus reagent such as, but not limited to, a triphenylphosphonium ylide. P is an appropriate protecting groups selected from,but not limited to, methyl, ethyl, isopropyl, tert-butyl, methoxybenzylor benzyl. The substituted biphenyl intermediate K is prepared fromIntermediate J by methodology such as, but not limited to, a Suzukireaction employing reactants such as, but not limited to, arylboronicacids or arylboronic esters catalyzed by a palladium(0) complex such as,but not limited to, tetrakis(triphenylphosphine)palladium ordichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct. The olefin of Intermediate K is reduced tofurnish Intermediate L by hydrogenation in the presence of a catalystsuch as, but not limited to, platinum-on-carbon or platinum oxide atatmospheric or elevated pressure. Alternatively, the reduction can beperformed using chiral catalysts and ligands such as, but not limitedto, those described in patent application WO2008031567. The protectinggroup P₃ can be removed with an acid selected from, but not limited to,TFA or HCl, or hydrogenation with a catalyst such as, but not limitedto, palladium-on-carbon under hydrogen to generate intermediate D or E.Alternatively, Intermediate E, or salts thereof, was prepared accordingto the route described in the U.S. Pat. No. 5,217,996 or in WO2008083967wherein P¹ is alkyl or benzyl.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form (including without limitationcapsules, tablets, pills, granules, powders or suppositories), or in aliquid form (including without limitation solutions, suspensions oremulsions). The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication. They are thus particularly suited for use in topical,including cosmetic, formulations well-known in the art. Such may containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof, in free form or inpharmaceutically acceptable salt form, exhibit valuable pharmacologicalproperties, e.g. neutral endopeptidase EC 3.4. 24.11 modulatingproperties, e.g. as indicated in in vitro and in vivo tests as providedin the next sections and are therefore indicated for therapy.

Compounds of the invention or a pharmaceutically acceptable saltthereof, may be useful in the treatment of an indication selected fromhypertension, pulmonary hypertension, pulmonary arterial hypertension,isolated systolic hypertension, resistant hypertension, peripheralvascular disease, heart failure, congestive heart failure, leftventricular hypertrophy, angina, renal insufficiency (diabetic ornon-diabetic), renal failure (including edema and salt retension),diabetic nephropathy, non-diabetic nephropathy, contrast inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure (including edema and salt retension), cyclicaloedema, Meniéres disease, hyperaldosteroneism (primary and secondary)and hypercalciuria, ascites, glaucoma, menstrual disorders, pretermlabour, pre-eclampsia, endometriosis, and reproductive disorders(especially male and female infertility, polycystic ovarian syndrome,implantation failure), asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders such as depression andpsychotic condition such as dementia and geriatric confusion, obesityand gastrointestinal disorders (especially diarrhea and irritable bowelsyndrome), wound healing (especially diabetic and venous ulcers andpressure sores), septic shock, gastric acid secretion dysfunctions,hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolicsyndrome, diabetic complications and atherosclerosis, male and femalesexual dysfunction. Thus, as a further embodiment, the present inventionprovides the use of a compound according to anyone of formulae I to V,or a pharmaceutically acceptable salt thereof. In a further embodiment,the therapy is selected from a disease which is associated with neutralendopeptidase EC 3.4. 24.11 activity. In another embodiment, the diseaseis selected from the afore-mentioned list, suitably hypertension,pulmonary hypertension, pulmonary arterial hypertension, isolatedsystolic hypertension, resistant hypertension, peripheral vasculardisease, heart failure, congestive heart failure, left ventricularhypertrophy, angina, renal insufficiency, renal failure (including edemaand salt retension), diabetic nephropathy, non-diabetic nephropathy,contrast induced nephropathy, type-2 diabetes, and diabeticcomplications and most suitably cardiovascular disorders, such ashypertension, renal insufficiency including edema and congestive heartfailure.

Thus, as a further embodiment, the present invention provides the use ofa compound according to anyone of formulae I to V, or a pharmaceuticallyacceptable salt thereof, in therapy. In a further embodiment, thetherapy is selected from a disease which may be treated by inhibitingneutral endopeptidase EC. 3.4. 24.11. activity.

In another embodiment, the invention provides a method of treating adisease which is associated with neutral endopeptidase EC 3.4. 24.11activity comprising administration of a therapeutically acceptableamount of a compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof. In a further embodiment, thedisease is selected from the afore-mentioned list, suitablyhypertension, pulmonary hypertension, pulmonary arterial hypertension,isolated systolic hypertension, resistant hypertension, peripheralvascular disease, heart failure, congestive heart failure, leftventricular hypertrophy, angina, renal insufficiency, renal failure(including edema and salt retension), diabetic nephropathy, non-diabeticnephropathy, contrast induced nephropathy, type-2 diabetes, and diabeticcomplications and most suitably cardiovascular disorders, such ashypertension, renal insufficiency including edema and congestive heartfailure.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the present invention can beassessed by the following in vitro & in vivo methods and/or by thefollowing in vitro & in vivo methods well-described in the art. See Afluorescence lifetime-based assay for protease inhibitor profiling onhuman kallikrein 7 Doering K, Meder G, Hinnenberger M, Woelcke J, Mayr LM, Hassiepen U Biomol Screen. 2009 January; 14(1):1-9.

In particular, the in vitro inhibition of recombinant human neutralendopeptidase (NEP, EC 3.4.24.11) can be determined as follows:

Recombinant human neutral endopeptidase (expressed in insect cells andpurified using standard methods, final concentration 7 pM) ispre-incubated with test compounds at various concentrations for 1 hourat room temperature in 10 mM sodium phosphate buffer at pH 7.4,containing 150 mM NaCl and 0.05% (w/v) CHAPS. The enzymatic reaction isstarted by the addition of a synthetic peptide substrateCys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 μM.Substrate hydrolysis leads to an increase fluorescence lifetime (FLT) ofPT14 measured by the means of a FLT reader as described by Doering etal. (2009). The effect of the compound on the enzymatic activity wasdetermined after 1 hour (t=60 min) incubation at room temperature. TheIC50 values, corresponding to the inhibitor concentration showing 50%reduction of the FLT values measured in absence of inhibitor, arecalculated from the plot of percentage of inhibition vs. inhibitorconcentration using non-linear regression analysis software.

Using the test assay (as described above) compounds of the inventionexhibited inhibitory efficacy in accordance to Table 1, provided infra.

TABLE 1 Inhibitory Activity of Compounds Compounds: Example # Human NEPIC₅₀ (nM) (2R,4S)-5-Biphenyl-4-yl-4-(3- 20 carboxy-propionylamino)-2-methyl-pentanoic acid; U.S. Pat. No. 5,217,996 Example 2 2 Example 4 0.3Example 6 3

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound according to anyone of formulae I to V, or a pharmaceuticallyacceptable salt thereof, and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition associated with neutral endopeptidase EC 3.4. 24.11 activity.

Products provided as a combined preparation include a compositioncomprising the compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof, and the other therapeuticagent(s) together in the same pharmaceutical composition, or thecompound according to anyone of formulae I to V, or a pharmaceuticallyacceptable salt thereof, and the other therapeutic agent(s) in separateform, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof, and another therapeuticagent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound according to anyone of formulae I to V, or a pharmaceuticallyacceptable salt thereof. In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (ii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent. Accordingly, the invention provides the useof a compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof, for treating a disease orcondition associated with neutral endopeptidase EC 3.4. 24.11 activity,wherein the medicament is prepared for administration with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or condition associated withneutral endopeptidase EC 3.4. 24.11 activity, wherein the medicament isadministered with a compound according to anyone of formulae I to V, ora pharmaceutically acceptable salt thereof.

The invention also provides a compound according to anyone of formulae Ito V, or a pharmaceutically acceptable salt thereof, for use in a methodof treating a disease or condition associated with neutral endopeptidaseEC 3.4. 24.11 activity, wherein the compound according to anyone offormulae I to V, or a pharmaceutically acceptable salt thereof, isprepared for administration with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition associated with neutral endopeptidase EC3.4. 24.11 activity, wherein the other therapeutic agent is prepared foradministration with a compound according to anyone of formulae I to V,or a pharmaceutically acceptable salt thereof. The invention alsoprovides a compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or condition associated with neutral endopeptidase EC3.4. 24.11 activity, wherein the compound according to anyone offormulae I to V or a pharmaceutically acceptable salt thereof, isadministered with another therapeutic agent. The invention also providesanother therapeutic agent for use in a method of treating a disease orcondition associated with neutral endopeptidase EC 3.4. 24.11 activity,wherein the other therapeutic agent is administered with a compoundaccording to anyone of formulae I to V, or a pharmaceutically acceptablesalt thereof.

The invention also provides the use of a compound according to anyone offormulae I to V or a pharmaceutically acceptable salt thereof, fortreating a disease or condition associated with neutral endopeptidase EC3.4. 24.11 activity, wherein the patient has previously (e.g. within 24hours) been treated with another therapeutic agent. The invention alsoprovides the use of another therapeutic agent for treating a disease orcondition associated with neutral endopeptidase EC 3.4. 24.11 activity,wherein the patient has previously (e.g. within 24 hours) been treatedwith a compound according to anyone of formulae I to V, or apharmaceutically acceptable salt thereof.

In one embodiment, the other therapeutic agent is selected from:

In one embodiment, the other therapeutic agent is selected from:HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker (ARBs,angiotensin II receptor antagonist), angiotensin converting enzyme (ACE)Inhibitor, a calcium channel blocker (CCB), an endothelin antagonist, arenin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, anobesity-reducing agent, an aldosterone receptor blocker, an endothelinreceptor blocker, an aldosterone synthase inhibitors (ASI), a CETPinhibitor and a phophodiesterase type 5 (PDE5) inhibitor.

The term “in combination with” a second agent or treatment includesco-administration of the compound of the invention (e.g., a compoundaccording to anyone of Formulae I-V or a compound otherwise describedherein) with the second agent or treatment, administration of thecompound of the invention first, followed by the second agent ortreatment and administration of the second agent or treatment first,followed by the compound of the invention.

The term “second agent” includes any agent which is known in the art totreat, prevent, or reduce the symptoms of a disease or disorderdescribed herein, e.g. a disorder or disease responsive to theinhibition of neutral endopeptidase, such as for example, hypertension,pulmonary hypertension, pulmonary arterial hypertension, isolatedsystolic hypertension, resistant hypertension, peripheral vasculardisease, heart failure, congestive heart failure, left ventricularhypertrophy, angina, renal insufficiency (diabetic or non-diabetic),renal failure (including edema and salt retension), diabeticnephropathy, non-diabetic nephropathy, contrast induced nephropathy,nephroic syndrome, glomerulonephritis, scleroderma, glomerularsclerosis, proteinurea of primary renal disease, renal vascularhypertention, diabetic retinopathy and end-stage renal disease (ESRD),endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure (including edema and salt retension), cyclicaloedema, Meniéres disease, hyperaldosteroneism (primary and secondary)and hypercalciuria, ascites, glaucoma, menstrual disorders, pretermlabour, pre-eclampsia, endometriosis, and reproductive disorders(especially male and female infertility, polycystic ovarian syndrome,implantation failure), asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders such as depression andpsychotic condition such as dementia and geriatric confusion, obesityand gastrointestinal disorders (especially diarrhea and irritable bowelsyndrome), wound healing (especially diabetic and venous ulcers andpressure sores), septic shock, the modulation of gastric acid secretion,the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2diabetes, metabolic syndrome, diabetic complications andatherosclerosis, male and female sexual dysfunction.

Examples of second agents include HMG-Co-A reductase inhibitors,angiotensin II receptor antagonists, angiotensin converting enzyme (ACE)Inhibitors, calcium channel blockers (CCB), endothelin antagonists,renin inhibitors, diuretics, ApoA-I mimics, anti-diabetic agents,obesity-reducing agents, aldosterone receptor blockers, endothelinreceptor blockers, aldosterone synthase inhibitors (ASI) and CETPinhibitors.

The term “HMG-Co-A reductase inhibitor” (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors)includes active agents that may be used to lower the lipid levelsincluding cholesterol in blood. Examples include atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptablesalts thereof.

The term “ACE-inhibitor” (also called angiotensin converting enzymeinhibitors) includes molecules that interrupt the enzymatic degradationof angiotensin Ito angiotensin II. Such compounds may be used for theregulation of blood pressure and for the treatment of congestive heartfailure. Examples include alacepril, benazepril, benazeprilat,captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat,fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril,ramipril, spirapril, temocapril, and trandolapril, or, pharmaceuticallyacceptables salt thereof.

The term “endothelin antagonist” includes bosentan (cf. EP 526708 A),tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable saltsthereof.

The term “renin inhibitor” includes ditekiren (chemical name:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-proly1-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L-histidinamide);terlakiren (chemical name:[R—(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);Aliskiren (chemical name:(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide)and zankiren (chemical name:[1S-[1R—[R*(R*)],2S*,3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide),or, hydrochloride salts thereof, or, SPP630, SPP635 and SPP800 asdeveloped by Speedel, or RO 66-1132 and RO 66-1168 of Formula (A) and(B):

or, pharmaceutically acceptable salts thereof.

The term “aliskiren”, if not defined specifically, is to be understoodboth as the free base and as a salt thereof, especially apharmaceutically acceptable salt thereof, most preferably ahemi-fumarate salt thereof.

An angiotensin II receptor antagonist or a pharmaceutically acceptablesalt thereof is understood to be an active ingredient which bind to theAT₁-receptor subtype of angiotensin II receptor but do not result inactivation of the receptor. As a consequence of the inhibition of theAT₁ receptor, these antagonists can, for example, be employed asantihypertensives or for treating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundswhich are selected from the group consisting of valsartan, losartan,candesartan, eprosartan, irbesartan, saprisartan, tasosartan,telmisartan, the compound with the designation E-1477 of the followingformula

the compound with the designation SC-52458 of the following formula

and the compound with the designation ZD-8731 of the following formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT₁-receptor antagonist are those agents which have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

The term “calcium channel blocker (CCB)” includes dihydropyridines(DHPs) and non-DHPs (e.g., diltiazem-type and verapamil-type CCBs).Examples include amlodipine, felodipine, ryosidine, isradipine,lacidipine, nicardipine, nifedipine, niguldipine, niludipine,nimodipine, nisoldipine, nitrendipine, and nivaldipine, and ispreferably a non-DHP representative selected from the group consistingof flunarizine, prenylamine, diltiazem, fendiline, gallopamil,mibefradil, anipamil, tiapamil and verapamil, or, pharmaceuticallyacceptable salts thereof. CCBs may be used as anti-hypertensive,anti-angina pectoris, or anti-arrhythmic drugs.

The term “diuretic” includes thiazide derivatives (e.g., chlorothiazide,hydrochlorothiazide, methylclothiazide, and chlorothalidon).

The term “ApoA-I mimic” includes D4F peptides (e.g., formulaD-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F)

The term “anti-diabetic agent” includes insulin secretion enhancers thatpromote the secretion of insulin from pancreatic β-cells. Examplesinclude biguanide derivatives (e.g., metformin), sulfonylureas (SU)(e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide,4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide), glibenclamide (glyburide), gliclazide,1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide,gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,glymidine, glypinamide, phenbutamide, and tolylcyclamide), orpharmaceutically acceptable salts thereof. Further examples includephenylalanine derivatives (e.g., nateglinide[N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine] (cf. EP 196222and EP 526171) of the formula

repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid] (cf. EP 589874, EP 147850 A2, in particular Example 11 on page 61,and EP 207331 A1); calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf. EP31058). Further examples include DPP-IV inhibitors, GLP-1 and GLP-1agonists.

DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IVgenerates a GLP-1 receptor antagonist and thereby shortens thephysiological response to GLP-1. GLP-1 is a major stimulator ofpancreatic insulin secretion and has direct beneficial effects onglucose disposal.

The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.DPP-IV inhibitors are in each case generically and specificallydisclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO95/15309, in each case in particular in the compound claims and thefinal products of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thesepublications. Preferred are those compounds that are specificallydisclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,respectively.

GLP-1 is an insulinotropic protein which is described, e.g., by W. E.Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in U.S. Pat. No.5,705,483.

The term “GLP-1 agonists” includes variants and analogs ofGLP-1(7-36)NH₂ which are disclosed in particular in U.S. Pat. No.5,120,712, U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO 91/11457and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. Furtherexamples include GLP-1(7-37), in which compound the carboxy-terminalamide functionality of Arg³⁶ is displaced with Gly at the 37^(th)position of the GLP-1(7-36)NH₂ molecule and variants and analogs thereofincluding GLN⁹-GLP-1(7-37), D-GLN⁹-GLP-1(7-37), acetyl LYS⁹-GLP-1(7-37),LYS¹⁸-GLP-1(7-37) and, in particular, GLP-1(7-37)OH, VAL⁸-GLP-1(7-37),GLY⁸-GLP-1(7-37), THR⁸-GLP-1(7-37), MET⁸-GLP-1(7-37) and4-imidazopropionyl-GLP-1. Special preference is also given to the GLPagonist analog exendin-4, described by Greig et al. in Diabetologia1999, 42, 45-50.

Also included in the definition “anti-diabetic agent” are insulinsensitivity enhancers which restore impaired insulin receptor functionto reduce insulin resistance and consequently enhance the insulinsensitivity. Examples include hypoglycemic thiazolidinedione derivatives(a g., glitazone,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]methyl}thiazolidine-2,4-dione(pioglitazone),5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297)).

Further anti-diabetic agents include, insulin signalling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),antidiabetic non-small molecule mimetic compounds and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT); compoundsinfluencing a dysregulated hepatic glucose production, like inhibitorsof glucose-6-phosphatase (G6 Pase), inhibitors offructose-1,6-bisphosphatase (F-1,6-Bpase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase(PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitorsof GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR;agonists of uncoupling proteins (UCPs); non-glitazone type PPARγagonists; dual PPARα/PPARγ agonists; antidiabetic vanadium containingcompounds; incretin hormones, like glucagon-like peptide-1 (GLP-1) andGLP-1 agonists; beta-cell imidazoline receptor antagonists; miglitol;α₂-adrenergic antagonists; and pharmaceutically acceptable saltsthereof.

The term “obesity-reducing agent” includes lipase inhibitors (e.g.,orlistat) and appetite suppressants (e.g., sibutramine and phentermine).

An aldosterone synthase inhibitor or a pharmaceutically acceptable saltthereof is understood to be an active ingredient that has the propertyto inhibit the production of aldosterone. Aldosterone synthase (CYP11B2)is a mitochondrial cytochrome P450 enzyme catalyzing the last step ofaldosterone production in the adrenal cortex, i.e., the conversion of11-deoxycorticosterone to aldosterone. The inhibition of the aldosteroneproduction with so-called aldosterone synthase inhibitors is known to bea successful variant to treatment of hypokalemia, hypertension,congestive heart failure, atrial fibrillation or renal failure. Suchaldosterone synthase inhibition activity is readily determined by thoseskilled in the art according to standard assays (e.g., US 2007/0049616).

The class of aldosterone synthase inhibitors comprises both steroidaland non-steroidal aldosterone synthase inhibitors, the later being mostpreferred.

Preference is given to commercially available aldosterone synthaseinhibitors or those aldosterone synthase inhibitors that have beenapproved by the health authorities.

The class of aldosterone synthase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds which are selected from the group consisting of thenon-steroidal aromatase inhibitors anastrozole, fadrozole (including the(+)-enantiomer thereof), as well as the steroidal aromatase inhibitorexemestane, or, in each case where applicable, a pharmaceuticallyacceptable salt thereof.

The most preferred non-steroidal aldosterone synthase inhibitor is the(+)-enantiomer of the hydrochloride of fadrozole (U.S. Pat. Nos.4,617,307 and 4,889,861) of formula

or, if appropriable, a pharmaceutically acceptable salt thereof.

A preferred steroidal aldosterone antagonist is eplerenone (cf. EP122232 A) of the formula

or Spironolactone; or, in each case, if appropriable, a pharmaceuticallyacceptable salt thereof.

Aldosterone synthase inhibitors useful in said combination are compoundsand analogs generically and specifically disclosed e.g. inUS2007/0049616, in particular in the compound claims and the finalproducts of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thispublication. Preferred aldosterone synthase inhibitors suitable for usein the present invention include, without limitation4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methylbenzonitrile;5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-methoxybenzyl)methylamide;4′-fluoro-6-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile;5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid butyl ester;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile;5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 4-fluorobenzyl ester;5-(4-Cyano-2-trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester;5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 2-isopropoxyethyl ester;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methylbenzonitrile;4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile;3-Fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile;cis-3-Fluoro-4-[7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl]benzonitrile;4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile;4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrileor in each case, the (R) or (S) enantiomer thereof; or if appropriable,a pharmaceutically acceptable salt thereof.

The term aldosterone synthase inhibitors also include compounds andanalogs disclosed in WO2008/076860, WO2008/076336, WO2008/076862,WO2008/027284, WO2004/046145, WO2004/014914, WO2001/076574.

Furthermore Aldosterone synthase inhibitors also include compounds andanalogs disclosed in U.S. patent applications US2007/0225232,US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068,US20090048241 and in PCT applications WO2006/005726, WO2006/128853,WO2006128851, WO2006/128852, WO2007065942, WO2007/116099, WO2007/116908,WO2008/119744 and in European patent application EP 1886695. Preferredaldosterone synthase inhibitors suitable for use in the presentinvention include, without limitation8-(4-Fluorophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-fluorobenzonitrile;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2,6-difluorobenzonitrile;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-methoxybenzonitrile;3-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)phthalonitrile;4-(8-(4-Cyanophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)naphthalene-1-carbonitrile;8-[4-(1H-Tetrazol-5-yl)phenyl]-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazineas developed by Speedel or in each case, the (R) or (S) enantiomerthereof; or if appropriable, a pharmaceutically acceptable salt thereof.

Aldosterone synthase inhibitors useful in said combination are compoundsand analogs generically and specifically disclosed e.g. in WO2009/156462 and WO 2010/130796, in particular in the compound claims andthe final products of the working examples, the subject-matter of thefinal products, the pharmaceutical preparations and the claims.

Preferred Aldosterone Synthase inhibitors suitable for combination inthe present invention include,3-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrilehydrochloride,1-(4-Methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole,2-(5-Benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole,5-(3-Cyano-1-methyl-1H-indol-2-yl)-nicotinic acid ethyl ester,N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide,Pyrrolidine-1-sulfonic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester,N-Methyl-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide,6-Chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile,6-Chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile,6-Chloro-1-methyl-2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile,Morpholine-4-carboxylic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide,N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide,C,C,C-Trifluoro-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide,N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-4-trifluoromethyl-benzenesulfonamide,N-[5-(3-Chloro-4-cyano-phenyl)-pyridin-3-yl]-1-phenyl-methanesulfonamide,N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)butane-1-sulfonamide,N-(1-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)ethyl)ethanesulfonamide,N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide,N-(cyclopropyl(5-(1H-indol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide,N-(cyclopropyl(5-naphtalen-1-yl-pyridin-3-yl)methyl)ethanesulfonamide,Ethanesulfonic acid[5-(6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridin-3-ylmethyl]-amideand Ethanesulfonic acid{[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethyl-amide.

The term “endothelin receptor blocker” includes bosentan.

The term “CETP inhibitor” refers to a compound that inhibits thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETPinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., U.S. Pat. No. 6,140,343). Examplesinclude compounds disclosed in U.S. Pat. No. 6,140,343 and U.S. Pat. No.6,197,786 (e.g.,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No.6,723,752 (e.g.,(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol);compounds disclosed in U.S. patent application Ser. No. 10/807,838;polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548;rosenonolactone derivatives and phosphate-containing analogs ofcholesteryl ester disclosed in J. Antibiot, 49 (8): 815-816 (1996), andBioorg. Med. Chem. Lett; 6:1951-1954 (1996), respectively. Furthermore,the CETP inhibitors also include those disclosed in WO2000/017165,WO2005/095409 and WO2005/097806.

CETP inhibitors useful in said combination are compounds and analogsgenerically and specifically disclosed e.g. in WO 2008/009435, WO2009/059943 and WO 2009/071509, in particular in the compound claims andthe final products of the working examples, the subject-matter of thefinal products, the pharmaceutical preparations and the claims.

A preferred PDE5 inhibitor is Sildenafil.

Second agent of particular interest include Endothelin antagonists,renin inhibitors, angiotensin II receptor antagonists, calcium channelblockers, diuretics, antidiabetic agents such as DPPIV inhibitors, andaldosterone synthase inhibitors.

In one embodiment, the invention provides a combination, in particular apharmaceutical combination, comprising a therapeutically effectiveamount of the compound according to the definition of formula I, II,III, IV or V or a pharmaceutically acceptable salt thereof, and one ormore therapeutically active agents selected from HMG-Co-A reductaseinhibitors, angiotensin II receptor antagonists, angiotensin convertingenzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelinantagonists, renin inhibitors, diuretics, ApoA-I mimics, anti-diabeticagents, obesity-reducing agents, aldosterone receptor blockers,endothelin receptor blockers, aldosterone synthase inhibitors (ASI) andCETP inhibitors.

In one embodiment, the invention provides a method of inhibiting neutralendopeptidase EC 3.4. 24.11 activity in a subject, wherein the methodcomprises administering to the subject a therapeutically effectiveamount of the compound according to the definition of formula I, II,III, IV or V or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a method of treating adisorder or a disease in a subject associated with neutral endopeptidaseEC 3.4. 24.11 activity, wherein the method comprises administering tothe subject a therapeutically effective amount of the compound accordingto the definition of formula I, II, III, IV or V or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the invention provides a method of treating adisorder or a disease in a subject associated with neutral endopeptidaseEC 3.4. 24.11 activity, wherein the disorder or the disease is selectedfrom hypertension, pulmonary hypertension, pulmonary arterialhypertension, isolated systolic hypertension, resistant hypertension,peripheral vascular disease, heart failure, congestive heart failure,left ventricular hypertrophy, angina, renal insufficiency (diabetic ornon-diabetic), renal failure (including edema and salt retension),diabetic nephropathy, non-diabetic nephropathy, contrast inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure (including edema and salt retension), cyclicaloedema, Meniéres disease, hyperaldosteroneism (primary and secondary)and hypercalciuria, ascites, glaucoma, menstrual disorders, pretermlabour, pre-eclampsia, endometriosis, and reproductive disorders(especially male and female infertility, polycystic ovarian syndrome,implantation failure), asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders such as depression andpsychotic condition such as dementia and geriatric confusion, obesityand gastrointestinal disorders (especially diarrhea and irritable bowelsyndrome), wound healing (especially diabetic and venous ulcers andpressure sores), septic shock, gastric acid secretion dysfunction,hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolicsyndrome, diabetic complications and atherosclerosis, male and femalesexual dysfunction.

In one embodiment, the invention provides a compound according to thedefinition of formula I, II, III, IV or V, or a pharmaceuticallyacceptable salt thereof, for use as a medicament.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula I, II, III, IV or V or apharmaceutically acceptable salt thereof, for the treatment of adisorder or disease in a subject associated with neutral endopeptidaseEC 3.4. 24.11 activity.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula I, II, III, IV or V, in themanufacture of a medicament for the treatment of a disorder or diseasein a subject characterized by an activity of neutral endopeptidase EC3.4. 24.11, wherein said disorder or disease is in particular selectedfrom hypertension, pulmonary hypertension, pulmonary arterialhypertension, isolated systolic hypertension, resistant hypertension,peripheral vascular disease, heart failure, congestive heart failure,left ventricular hypertrophy, angina, renal insufficiency (diabetic ornon-diabetic), renal failure (including edema and salt retension),diabetic nephropathy, non-diabetic nephropathy, contrast inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure (including edema and salt retension), cyclicaloedema, Meniéres disease, hyperaldosteroneism (primary and secondary)and hypercalciuria, ascites, glaucoma, menstrual disorders, pretermlabour, pre-eclampsia, endometriosis, and reproductive disorders(especially male and female infertility, polycystic ovarian syndrome,implantation failure), asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders such as depression andpsychotic condition such as dementia and geriatric confusion, obesityand gastrointestinal disorders (especially diarrhea and irritable bowelsyndrome), wound healing (especially diabetic and venous ulcers andpressure sores), septic shock, gastric acid secretion dysfunction,hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolicsyndrome, diabetic complications and atherosclerosis, male and femalesexual dysfunction.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula I, II, III, IV or V, or apharmaceutically acceptable salt thereof, for the treatment of adisorder or disease in a subject characterized by an activity of neutralendopeptidase EC 3.4. 24.11, wherein the disorder or disease is selectedfrom hypertension, pulmonary hypertension, pulmonary arterialhypertension, isolated systolic hypertension, resistant hypertension,peripheral vascular disease, heart failure, congestive heart failure,left ventricular hypertrophy, angina, renal insufficiency (diabetic ornon-diabetic), renal failure (including edema and salt retension),diabetic nephropathy, non-diabetic nephropathy, contrast inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure (including edema and salt retension), cyclicaloedema, Meniéres disease, hyperaldosteroneism (primary and secondary)and hypercalciuria, ascites, glaucoma, menstrual disorders, pretermlabour, pre-eclampsia, endometriosis, and reproductive disorders(especially male and female infertility, polycystic ovarian syndrome,implantation failure), asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders such as depression andpsychotic condition such as dementia and geriatric confusion, obesityand gastrointestinal disorders (especially diarrhea and irritable bowelsyndrome), wound healing (especially diabetic and venous ulcers andpressure sores), septic shock, gastric acid secretion dysfunction,hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolicsyndrome, diabetic complications and atherosclerosis, male and femalesexual dysfunction

Exemplification of the Invention:

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Exemplification of the Invention:

Abbreviations: ATP: adenosine 5′-triphosphate AS: Aldosterone Synthasebr: broad bs: broad singlet Ac: Acetyl Atm: atmosphere Aq: aqueouscalcd: calculated Bn: benzyl Boc: tert-butoxycarbonyl d: doublet DAST:(diethylamino)sulfur trifluoride dd: doublet of doublets DCM:dichloromethane DMF: N,N-dimethylformamide DMSO: dimethylsulfoxideDIPEA: N,N-diisopropylethylamine DMAP: N,N- dimethylaminopyridine DAD:diode array detector DTT: dithiothreitol EDTA: ethylenediaminetetraacetic ESI: electrospray ionization acid Et and EtOAc: ethyl andethyl EDC: N-Ethyl-N′-(3- acetate dimethylaminopropyl)carbodiimidehydrochloride HPLC: high pressure liquid LC and LCMS: liquidchromatography chromatography and liquid HPLC-RT (retention time)chromatography and mass spectrometry H: Hour(s) hrs: hours IR: infraredLDA: lithium diisopropylamide MeOD: methanol-d4 MeOH: methanol MS: massspectrometry m: multiplet min: minutes m/z: mass to charge ratio Ms:mesyl Me: methyl M and mM: Molar and millimole(s) Mg: milligram n.d.:not determined NMR: nuclear magnetic resonance ppm: parts per million Prand iPr: propyl and isopropyl Ph: Phenyl Pd/C: Palladium on Carbom RT:room temperature RP: reverse phase q: quartet s: singlet t: triplet TFA:trifluoroacetic acid THF: tetrahydrofuran TMSCl: trimethylsilyl chlorideTEA: triethylamine Tf: triflate tBu: tert-butyl TLC: thin layerchromatography Tris•HCl: aminotris(hydroxy- methyl) methanehydrochloride μL, mL and L: microlitre, UV: ultraviolet millilitre andlitre

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

HPLC Condition A:

Column: INERTSIL C8-3, 3 μm×33 mm×3.0 mm at 50° C.

Flow rate: 2 mL/min

Mobile phase: H₂O (5 mM NH4+HCOO—)

Gradient: linear gradient from 5% to 95% MeCN/MeOH (1:1) in 2 min

Detection: DAD-UV at 210-400 nm

The relative stereochemistry was determined using two dimensional NMR.Under the reaction condition, it would be unexpected that thestereocenter bearing the bisphenyl-methyl group racemize. Therefore, theabsolute stereochemistry was determined based on the relativestereochemistry and the stereochemistry of the stereocenter bearing thebisphenyl-methyl group.

Example 1 Synthesis of(2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester

To a stirred solution of(S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethylester hydrochloric acid salt (200 mg, 0.52 mmol) anddihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH₂Cl₂ was addedpyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours.The reaction mixture was acidified to pH=3 with 1M HCl. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90%heptane 10% EtOH+0.1% TFA), collected a peak at 5.7 minutes, to give 25mg(2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A):1.52 min.

Example 2 Synthesis of(2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid

To a stirred solution of(2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester (25 mg, 0.056 mmol) in 2 ml EtOH was added 1 ml ofaqueous 1M NaOH and the solution was stirred for an hour. The reactionmixture was acidified to pH=2 to 3 with aqueous 1M HCl. Solvent wasremoved under reduced pressure and the residue was purified by RP-HPLCto give 14 mg(2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid. MS m/z 418.2 (M+H), 416.2 (M−H). LC/MS (Condition A): 1.18 min ¹HNMR (400 MHz, DMSO-d6): 0.98-1.00 (d, J=6.82 Hz, 3H), 1.39-1.45 (m, 1H),1.71-1.78 (m, 1H), 2.18-2.38 (m, 5H), 2.67-2.76 (m, 2H), 3.97-4.07 (m,1H), 7.26-7.28 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.45-7.49 (t,J=7.83 Hz, 1H), 7.60-7.64 (m, 3H), 7.70-7.71 (t, J=1.77 Hz, 1H),7.75-7.77 (d, J=8.84 Hz, 1H), 12.08 (br s, 2H).

Example 3 Synthesis of(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester

To a stirred solution of(S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethylester hydrochloric acid salt (200 mg, 0.52 mmol) anddihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH₂Cl₂ was addedpyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours.The reaction mixture was acidified to pH=3 with 1M HCl. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90%heptane 10% EtOH+0.1% TFA), collected a peak at 3.9 minutes, to give 50mg(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A):1.52 min. ¹H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H),1.09-1.13 (t, J=7.07 Hz, 3H), 1.34-1.42 (m, 1H), 1.72-1.79 (m, 1H),2.24-2.29 (m, 2H), 2.36-2.40 (m, 21-9, 2.64-2.74 (m, 2H), 3.33 (s, 1H),3.86-3.93 (m, 1H), 3.95-4.01 (q, J=7.33 Hz, 14.40 Hz, 2H), 7.25-7.27 (m,2H), 7.39-7.41 (m, 1H), 7.46-7.50 (t, J=7.58 Hz, 1H), 7.61-7.64 (m, 3H),7.70 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.08 (br s, 2H).

Example 4 Synthesis of(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid

To a stirred solution of(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester (20 mg, 0.045 mmol) in 2 ml EtOH was added 1 ml ofaqueous 1M NaOH and the solution was stirred for an hour. The reactionmixture was acidified to pH=2 to 3 with aqueous 1M HCl. Solvent wasremoved under reduced pressure and the residue was purified by RP-HPLCto give 10 mg(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid. LC/MS m/z 418.3 (M+H), 419.4 (M−H). LC/MS (Condition A): 1.21 min.¹H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.30-1.37 (m,1H), 1.73-1.80 (m, 1H), 2.24-2.39 (m, 5H), 2.66-2.73 (m, 2H), 3.90-3.98(m, 1H), 7.25-7.27 (d, J=8.08 Hz, 2H), 7.39-7.41 (m, 1H), 7.45-7.49 (t,J=7.83 Hz, 1H), 7.60-7.64 (m, 3H), 7.70-7.71 (t, J=2.02 Hz, 1H),7.75-7.77 (d, J=8.59 Hz, 1H), 12.04 (br s, 2H).

Example 5 Synthesis of(S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester

To a solution of(S)-4-amino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethylester hydrochloric acid salt (240 mg, 0.703 mmol) in pyridine/DCM (1ml/1 ml) was added succinic anhydride (84 mg, 0.843 mmol) and stirred atroom temperature for 1 hour. Then, the mixture was concentrated underreduced pressure, and the residue was purified by RP-HPLC to give(S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester. HPLC Retention time 1.29 minutes (condition A): MS442.4 (M+1)

Example 6 Synthesis of(S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoicacid

To(S)-4-(3-carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester was added 1M NaOH (2 ml) and stirred at roomtemperature for 2 hours. Then, to the mixture was added 2 ml of 1M HCland concentrated under reduced pressure. The obtained residue waspurified by RP-HPLC(H2O(0.1% TFA)/CH₃CN) to afford 110 mg of whitepowder. HPLC Retention time 0.86 minutes (condition A): MS 414.1 (M+1)¹H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 3H) 1.28-1.48 (m, 1′-1)1.66-1.84 (m, 1H) 2.24-2.39 (m, 5H) 2.63-2.75 (m, 2H) 3.75-4.02 (m,4′-1) 6.97-7.04 (m, 1H) 7.09 (d, J=7.58 Hz, 1H) 7.16-7.22 (m, 2H)7.24-7.29 (m, 1H) 7.29-7.35 (m, 1H) 7.35-7.41 (m, 2H) 7.77 (d, J=8.59Hz, 1H).

Intermediate 1: Synthesis of(S)-4-Amino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethylester hydrochloric acid salt

The mixture of(R)-5-(4-bromo-phenyl)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoicacid ethyl ester (600 mg, 1.455 mmol), 2-methoxyphenylboronic acid (243mg, 1.601 mmol) and1,1′-[Bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (59.4 mg, 0.073 mmol) in toluene (15 ml) was bubblewith nitrogen for 10 minutes, then the solution of sodium carbonate (2M,1.455 ml) was added. The resulting mixture was heated to 100° C. for 2hours. After cooling down to room temperature, the mixture was dilutedwith ice-water and extracted with ethyl acetate. The combined organicphase was washed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The obtained residue was purifiedby column chromatography to afford 600 mg pale brown oil. HPLC Retentiontime 1.49 minutes (condition A): MS 457.4 (M+18)

Next, to a solution of(R)-4-tert-butoxycarbonylamino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pent-2-enoicacid ethyl ester (500 mg, 1.138 mmol) in ethanol (15 ml) was added Pt/C(10%, 50 mg) and stirred at room temperature overnight under hydrogen.Then, the mixture was filtered through a pad of celite and washed withethanol. The filtrate was concentrated to afford 471 mg colorless oil.The obtained material was used for next step without furtherpurification. HPLC Retention time 1.53 minutes (condition A): MS 459.5(M+18)

Next, to a solution of(S)-4-tert-butoxycarbonylamino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester (473 mg, 1.017 mmol) in DCM (5 ml) was added HCl indioxane (4M, 1 ml), and the resulting mixture was stirred at roomtemperature for 2 hours. Then, the mixture was concentrated on underreduced pressure. The obtained residue was used for next step withoutfurther purification. HPLC Retention time 1.28 minutes (condition A): MS342.4 (M+1).

Intermediate 2: Synthesis of(S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethylester hydrochloric acid salt

Intermediate 2 was prepared using same procedure as described forintermediate 1. For intermediate 2,3-chlorophenylboronic acid was usedinstead of 2-methoxyphenylboronic acid described in intermediate 1. HPLCRetention time 1.59 minutes (condition A): MS 346.2 (M+1).

It can be seen that the compounds of the invention are useful asinhibitors of Neutral endopeptidase (EC 3.4.24.11) activity andtherefore useful in the treatment of diseases and conditions associatedwith Neutral endopeptidase (EC 3.4.24.11) activity such as the diseasesdisclosed herein.

It will be understood that the invention has been described by way ofexample only and modifications may be made whilst remaining within thescope and spirit of the invention.

The following are further embodiments of the invention:

Embodiment 1

A compound of the formula (I):

wherein:X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl;R¹ is H or C₁₋₆ alkyl;R² for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl;A¹ is a linear C₁₋₄ alkylene;R³ for each occurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo,C₁₋₇alkyl or halo-C₁₋₇alkyl; orn is an integer from 1 to 5;s is 0 or an integer from 1 to 4; ora pharmaceutically acceptable salt thereof.

Embodiment 2

The compound according to embodiment 1 of Formula II:

wherein:X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl;R¹ is H or C₁₋₆ alkyl;R² for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl;A¹ is a linear C₁₋₄ alkylene;R³ for each occurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo,C₁₋₇alkyl or halo-C₁₋₇alkyl; orn is an integer from 1 to 5;s is 0 or an integer from 1 to 4; ora pharmaceutically acceptable salt thereof.

Embodiment 3

The compound according to embodiment 1 of Formula III:

wherein:p is 0, 1, 2, 3 or 4 and R^(2a) is halo; ora pharmaceutically acceptable salt thereof.

Embodiment 4

The compound according to embodiment 1, 2 or 3 of Formula IV:

wherein:p is 0, 1, 2, 3 or 4 and R^(2a) is halo; ora pharmaceutically acceptable salt thereof.

Embodiment 5

The compound according to embodiment 3 or 4 wherein R^(2a) is chloro andp is 0, or a pharmaceutically acceptable salt thereof.

Embodiment 6

The compound according to embodiment 1 of Formula V:

wherein:p is 0, 1, 2, 3 or 4 and R^(2b) is C₁₋₆-alkoxy; ora pharmaceutically acceptable salt thereof.

Embodiment 7

The compound according to embodiment 6 wherein R^(2b) is methoxy and pis 0, or a pharmaceutically acceptable salt thereof.

Embodiment 8

The compound of any of the preceding embodiments wherein

X and X′ represent independently OH or O—C₁₋₆-alkyl;

R¹ is H or C₁₋₆-alkyl;

A¹ is CH₂—CH₂;

s is 0;

a pharmaceutically acceptable salt thereof.

Embodiment 9

The compound of any of the preceding embodiments wherein R¹ isC₁₋₆-alkyl; or a pharmaceutically acceptable salt thereof.

Embodiment 10

A pharmaceutical composition comprising a compound according to any oneof embodiments 1 to 9, or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable carriers.

Embodiment 11

A combination comprising: a compound according to any one of embodiments1 to 9 or a pharmaceutically acceptable salt thereof and one or moretherapeutically active agents selected from HMG-Co-A reductaseinhibitor, an anigiotensin receptor blocker, angiotensin convertingenzyme Inhibitor, a calcium channel blocker, an endothelin antagonist, arenin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, anobesity-reducing agent, an aldosterone receptor blocker, an endothelinreceptor blocker, an aldosterone synthase inhibitors, a CETP inhibitorand a phophodiesterase type 5 (PDE5) inhibitor.

Embodiment 12

A method of inhibiting neutral endopeptidase EC. 3.4. 24.11. activity ina subject in need thereof, comprising: administering to the subject atherapeutically effective amount of the compound according to any one ofembodiments 1 to 9 or a pharmaceutically acceptable salt thereof.

Embodiment 13

A method of treating a disorder or a disease associated with neutralendopeptidase EC. 3.4. 24.11. activity in a subject in need thereof,comprising: administering to the subject a therapeutically effectiveamount of the compound according to any one of embodiments 1 to 9 or apharmaceutically acceptable salt thereof.

Embodiment 14

The method according to embodiment 13, wherein the disorder or thedisease is selected from hypertension, resistant hypertension, pulmonaryhypertension, pulmonary arterial hypertension, isolated systolichypertension, peripheral vascular disease, heart failure, congestiveheart failure, left ventricular hypertrophy, angina, renalinsufficiency, renal failure, diabetic nephropathy, non-diabeticnephropathy, contrast-induced nephropathy, nephroic syndrome,glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea ofprimary renal disease, renal vascular hypertention, diabetic retinopathyand end-stage renal disease (ESRD), endothelial dysfunction, diastolicdysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy,supraventricular and ventricular arrhythmias, atrial fibrillation (AF),cardiac fibrosis, atrial flutter, detrimental vascular remodeling,plaque stabilization, myocardial infarction (MI), renal fibrosis,polycystic kidney disease (PKD), renal failure, cyclical oedema,Meniéres disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma,menstrual disorders, preterm labour, pre-eclampsia, endometriosis, andreproductive disorders, asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders, depression, psychoticcondition, dementia, geriatric confusion, obesity, gastrointestinaldisorders, wound healing, septic shock, gastric acid secretiondysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2diabetes, metabolic syndrome, diabetic complications, atherosclerosis,and male and female sexual dysfunction.

Embodiment 15

The compound according to any one of embodiments 1 to 9, or apharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 16

Use of the compound according to any one of embodiments 1 to 9, or apharmaceutically acceptable salt thereof, for the treatment of adisorder or disease associated with neutral endopeptidase EC. 3.4.24.11. activity in a subject in need of such treatment.

Embodiment 17

The use of embodiment 16, wherein the disorder or disease is selectedfrom hypertension, resistant hypertension, pulmonary hypertension,pulmonary arterial hypertension, isolated systolic hypertension,peripheral vascular disease, heart failure, congestive heart failure,left ventricular hypertrophy, angina, renal insufficiency, renalfailure, diabetic nephropathy, non-diabetic nephropathy,contrast-induced nephropathy, nephroic syndrome, glomerulonephritis,scleroderma, glomerular sclerosis, proteinurea of primary renal disease,renal vascular hypertention, diabetic retinopathy and end-stage renaldisease (ESRD), endothelial dysfunction, diastolic dysfunction,hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricularand ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure, cyclical oedema, Meniéres disease,hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrualdisorders, preterm labour, pre-eclampsia, endometriosis, andreproductive disorders, asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders, depression, psychoticcondition, dementia, geriatric confusion, obesity, gastrointestinaldisorders, wound healing, septic shock, gastric acid secretiondysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2diabetes, metabolic syndrome, diabetic complications, atherosclerosis,and male and female sexual dysfunction.

What is claimed is:
 1. A compound of Formula IV:

wherein: X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl; R¹ is H or C₁₋₆ alkyl; R²for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl; A¹ is —CH₂—CH₂—; R³ for eachoccurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo, C₁₋₇alkylor halo-C₁₋₇alkyl; or s is 0; p is 0, 1, 2, 3 or 4 and R^(2a) is halo;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1 wherein R^(2a) is chloro and p is 0, or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1 wherein X and X¹represent independently OH or O—C₁₋₆-alkyl; R¹ is H or C₁₋₆-alkyl; or apharmaceutically acceptable salt thereof.
 4. The compound of claim 3wherein R¹ is C₁₋₆-alkyl; or a pharmaceutically acceptable salt thereof.5. A pharmaceutical composition comprising a compound according to claim1, or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers.
 6. A combination comprising: acompound according to claim 1 or a pharmaceutically acceptable saltthereof and one or more therapeutically active agents selected fromHMG-Co-A reductase inhibitor, an anigiotensin receptor blocker,angiotensin converting enzyme Inhibitor, a calcium channel blocker, anendothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic,an anti-diabetic agent, an obesity-reducing agent, an aldosteronereceptor blocker, an endothelin receptor blocker, an aldosteronesynthase inhibitors, a CETP inhibitor and a phophodiesterase type 5(PDE5) inhibitor.
 7. A method of inhibiting neutral endopeptidase EC.3.4. 24.11. activity in a subject in need thereof, comprising:administering to the subject a therapeutically effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 8. A method of treating a disorder or a disease associated withneutral endopeptidase EC. 3.4. 24.11. activity in a subject in needthereof, comprising: administering to the subject a therapeuticallyeffective amount of the compound according to claim 1 or apharmaceutically acceptable salt thereof.
 9. The method according toclaim 8, wherein the disorder or the disease is selected fromhypertension, resistant hypertension, pulmonary hypertension, pulmonaryarterial hypertension, isolated systolic hypertension, peripheralvascular disease, heart failure, congestive heart failure, leftventricular hypertrophy, angina, renal insufficiency, renal failure,diabetic nephropathy, non-diabetic nephropathy, contrast-inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure, cyclical oedema, Menières disease,hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrualdisorders, preterm labour, pre-eclampsia, endometriosis, andreproductive disorders, asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders, depression, psychoticcondition, dementia, geriatric confusion, obesity, gastrointestinaldisorders, wound healing, septic shock, gastric acid secretiondysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2diabetes, metabolic syndrome, diabetic complications, atherosclerosis,and male and female sexual dysfunction.
 10. The compound according toclaim 1, selected from(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid ethyl ester; and(2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoicacid; or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition comprising a compound according to claim 10,or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers.
 12. A compound of Formula V:

wherein: X and X¹ are independently OH, —O—C₁₋₇alkyl, —NR^(a)R^(b),—NHS(O)₂—C₁₋₇alkyl or —NHS(O)₂-benzyl, wherein R^(a) and R^(b) for eachoccurrence are independently H or C₁₋₇alkyl; R¹ is H or C₁₋₆ alkyl; R²for each occurrence is independently C₁₋₆-alkoxy, hydroxy, halo,C₁₋₆-alkyl, cyano or halo-C₁₋₆-alkyl; A¹ is a linear C₁₋₄ alkylene; R³for each occurrence is independently halo, hydroxy, C₁₋₇alkoxy, halo,C₁₋₇alkyl or halo-C₁₋₇alkyl; s is 0 or an integer from 1 to 4; p is 0,1, 2, 3 or 4 and R^(2b) is C₁₋₆-alkoxy; or a pharmaceutically acceptablesalt thereof.
 13. The compound according to claim 12 wherein R^(2b) ismethoxy and p is 0, or a pharmaceutically acceptable salt thereof. 14.The compound of claim 12 wherein X and X¹ represent independently OH orO—C₁₋₆-alkyl; R¹ is H or C₁₋₆-alkyl; A¹ is CH₂—CH₂; s is 0; apharmaceutically acceptable salt thereof.
 15. The compound of claim 12wherein R¹ is C₁₋₆-alkyl; or a pharmaceutically acceptable salt thereof.16. A pharmaceutical composition comprising a compound according toclaim 12, or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers.
 17. A combination comprising: acompound according to claim 12 or a pharmaceutically acceptable saltthereof and one or more therapeutically active agents selected fromHMG-Co-A reductase inhibitor, an anigiotensin receptor blocker,angiotensin converting enzyme Inhibitor, a calcium channel blocker, anendothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic,an anti-diabetic agent, an obesity-reducing agent, an aldosteronereceptor blocker, an endothelin receptor blocker, an aldosteronesynthase inhibitors, a CETP inhibitor and a phophodiesterase type 5(PDE5) inhibitor.
 18. A method of inhibiting neutral endopeptidase EC.3.4. 24.11. activity in a subject in need thereof, comprising:administering to the subject a therapeutically effective amount of thecompound according to claim 12 or a pharmaceutically acceptable saltthereof.
 19. A method of treating a disorder or a disease associatedwith neutral endopeptidase EC. 3.4. 24.11. activity in a subject in needthereof, comprising: administering to the subject a therapeuticallyeffective amount of the compound according to claim 12 or apharmaceutically acceptable salt thereof.
 20. The method according toclaim 19, wherein the disorder or the disease is selected fromhypertension, resistant hypertension, pulmonary hypertension, pulmonaryarterial hypertension, isolated systolic hypertension, peripheralvascular disease, heart failure, congestive heart failure, leftventricular hypertrophy, angina, renal insufficiency, renal failure,diabetic nephropathy, non-diabetic nephropathy, contrast-inducednephropathy, nephroic syndrome, glomerulonephritis, scleroderma,glomerular sclerosis, proteinurea of primary renal disease, renalvascular hypertention, diabetic retinopathy and end-stage renal disease(ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophiccardiomyopathy, diabetic cardiac myopathy, supraventricular andventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis,atrial flutter, detrimental vascular remodeling, plaque stabilization,myocardial infarction (MI), renal fibrosis, polycystic kidney disease(PKD), renal failure, cyclical oedema, Menières disease,hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrualdisorders, preterm labour, pre-eclampsia, endometriosis, andreproductive disorders, asthma, obstructive sleep apnea, inflammation,leukemia, pain, epilepsy, affective disorders, depression, psychoticcondition, dementia, geriatric confusion, obesity, gastrointestinaldisorders, wound healing, septic shock, gastric acid secretiondysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2diabetes, metabolic syndrome, diabetic complications, atherosclerosis,and male and female sexual dysfunction.